Aromatic amides

ABSTRACT

Aromatic and heteroaromatic amides of the formula 
                 
 
where R 1 , R 2  and R 3  can be alkyl, X is alkylene, and R 4  is an unsubstituted or substituted aromatic or heteroaromatic group such as naphthyl or fluorenyl,
 
are CNS agents useful for treating pain, depression, anxiety, seizures, and schizophrenia.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 filing of PCT/GB00/01788 filed May 10, 2000,priority based on Provisional Application Ser. No. 60/133,359 filed May10, 1999.

FIELD OF THE INVENTION

This invention provides aromatic amides which are useful CNS agents,especially for treating depression, pain, anxiety, schizophrenia andseizure disorders.

BACKGROUND OF THE INVENTION

Disorders of the central nervous system have become one of the mostcommon and most debilitating diseases currently afflicting mankind.Specific disorders such as depression and schizophrenia are now known tobe common afflictions, and are routinely diagnosed. These diseasesresult in significant losses of an individual's ability to work and tocarry out normal daily activities, and in many cases require long termhospitalization or institutionalization. Only recently have newtreatments, such as the selective serotonin re-uptake inhibitors forexample, become available and are effective for many people.Unfortunately, such agents are not effective for all cases ofdepression, and indeed can lead to significant adverse reactions in somepatients.

Other CNS disorders, such as chronic pain and seizure disorders, areonly marginally treatable, and such treatments often are associated withunacceptably high health risks, for instance long term use of narcoticanalgesics to treat chronic pain generally results in addiction to thedrug being employed, the results of which can be devastating to thepatient.

Accordingly, the need continues for new medicines that will effectivelytreat CNS disorders without imposing unacceptable liability and riskissues. I have now discovered a series of aromatic amides which can beutilized to treat these CNS disorders, and which have a very goodrisk-to-benefit ratio. The invention compounds are alkyl amides havingan aromatic group attached to the amide nitrogen atom.

Several N-aryl alkylamides are known in the prior art. For example,Ronsisvalle et al. described a series of analgesic N-thienyl acetamidesin Eur. J. Med. Chem. 3: 553-559, 1998.

U.S. Pat. No. 4,203,988 discloses certain N-pyridyl amide derivatives asinhibitors of gastric secretion, while U.S. Pat. No. 3,163,645 disclosesN-pyridyl amides as analgesics. U.S. Pat. No. 5,372,931 disclosesN-alkoxyphenyl and N-alkoxynaphtyl amides as useful in certainanalytical and diagnostic methods.

Elslager et al., in J. Med. Chem. 9: 378-91, 1966, describe certainN-naphthyl amides as useful as intermediates in the synthesis of arylazosubstituted naphthyl alkylenediamines. Similarly, Elslarger et al.,described certain N-quinolyl amides in J. Med. Chem. 12: 600-7, 1966.

The compounds provided by this invention are characterized as novelN-aryl amides having good CNS activities, and are thus useful fortreating depression, anxiety, pain, schizophrenia, and seizure disorderssuch as epilepsy.

SUMMARY OF THE INVENTION

This invention provides N-aryl alkylamides defined by Formula I

wherein:

-   R¹ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl;-   R² and R³ independently are hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy,    phenyl or benzyl, or taken together with the nitrogen to which they    are attached complete a ring having from 4 to 7 ring atoms, one    optionally being oxygen; X is (CH₂)_(n), CHMe-(CH₂)_(n-1) or    (CH₂)_(n-1)—CHMe, n is 1, 2 or 3;-   R⁴ is an aromatic or heteroaromatic group selected from    wherein R⁵ is hydrogen, halogen, C₁-C₄ alkyl, nitro, N₃ or CF₃ and    R⁶ is hydrogen, C₁₋₄ alkyl, —(C═O)Me, —(C═O)NH₂,    and the pharmaceutically acceptable salts thereof.    Preferred invention compounds have Formula I wherein R¹. R² and R³    independently are C₁-C₄ alkyl, and R is naphthyl, substituted    naphthyl, fluorene or substituted fluorene. Also preferred are the    compounds of Formula I wherein n is 2 or 3.

Another embodiment of this invention is a pharmaceutical formulationcomprising a compound of Formula I admixed with a pharmaceuticallyacceptable carrier, diluent or carrier therefor.

The compounds of the instant invention are useful for the treatment ofCNS disorders including neurodegenerative disorders, pain, depression,convulsions, anxiety, schizophrenia and seizures.

Neurodegenerative disorders include, for example, Alzheimer's disease,Huntington's disease, Parkinson's disease, and Amyotrophic LateralSclerosis.

The present invention also covers treating neurodegenerative disorderstermed acute brain injury. These include but are not limited to: stroke,head trauma, and asphyxia.

Stroke refers to a cerebral vascular disease and may also be referred toas a cerebral vascular incident (CVA) and includes acute thromboembolicstroke. Stroke includes both focal and global ischemia. Also, includedare transient cerebral ischemic attacks and other cerebral vascularproblems accompanied by cerebral ischemia. A patient undergoing carotidendarterectomy specifically or other cerebrovascular or vascularsurgical procedures in general, or diagnostic vascular proceduresincluding cerebral angiography and the like.

Other incidents are head trauma, spinal cord trauma, or injury fromgeneral anoxia, hypoxia, hypoglycemia, hypotension as well as similarinjuries seen during procedures from embole, hyperfusion, and hypoxia.

The instant invention would be useful in a range of incidents, forexample, during cardiac bypass surgery, in incidents of intracranialhemorrhage, in perinatal asphyxia, in cardiac arrest, and statusepilepticus.

Pain refers to acute as well as chronic pain.

Acute pain is usually short-lived and is associated with hyperactivityof the sympathetic nervous system. Examples are postoperative pain andallodynia.

Chronic pain is usually defined as pain persisting from 3 to 6 monthsand includes somatogenic pains and psychogenic pains. Other pain isnociceptive.

Still other pain is caused by injury or infection of peripheral sensorynerves. It includes, but is not limited to pain from peripheral nervetrauma, herpes virus infection, diabetes mellitus, causalgia, plexusavulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain isalso caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Neuropathic pain includes, but is not limited to paincaused by nerve injury such as, for example, the pain diabetics sufferfrom.

Psychogenic pain is that which occurs without an organic origin such aslow back pain, atypical facial pain, and chronic headache.

Other types of pain are: inflammatory pain, osteoarthritic pain,trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legsyndrome, acute herpetic and postherpetic neuralgia, causalgia, brachialplexus avulsion, occipital neuralgia, gout, phantom limb, burn, IBS andother forms of neuralgia, neuropathic and idiopathic pain syndrome.

A skilled physician will be able to determine the appropriate situationin which subjects are susceptible to or at risk of, for example, strokeas well as suffering from stroke for administration by methods of thepresent invention.

The compounds of the invention are also useful in the treatment ofdepression. Depression can be the result of organic disease, secondaryto stress associated with personal loss, or idiopathic in origin. Thereis a strong tendency for familial occurrence of some forms of depressionsuggesting a mechanistic cause for at least some forms of depression.The diagnosis of depression is made primarily by quantification ofalterations in patients' mood. These evaluations of mood are generallyperformed by a physician or quantified by a neuropsychologist usingvalidated rating scales, such as the Hamilton Depression Rating Scale orthe Brief Psychiatric Rating Scale. Numerous other scales have beendeveloped to quantify and measure the degree of mood alterations inpatients with depression, such as insomnia, difficulty withconcentration, lack of energy, feelings of worthlessness, and guilt. Thestandards for diagnosis of depression as well as all psychiatricdiagnoses are collected in the Diagnostic and Statistical Manual ofMental Disorders (Fourth Edition) referred to as the DSM-IV-R manualpublished by the American Psychiatric Association, 1994.

The compounds of the instant invention are also expected to be useful inthe treatment of anxiety, panic, schizophrenia and seizures asdemonstrated by means of standard pharmacological procedures.

The invention also provides a method for treating CNS disorders inmammals, comprising administering a CNS effective amount of a compoundof Formula I to a mammal in need of treatment.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “C₁-C₄ alkyl” means straight and branchedcarbon chains having from 1 to 4 carbon atoms, for example methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.

-   “C₂C₄ alkenyl” means ethylene, 2-propylene and 2- or 3-butylene.-   “Halo” means fluoro, chloro, bromo and iodo.-   “Substituted aryl” and “substituted heteroaryl” means any of the    cyclic ring systems described above having R⁵ other than hydrogen,    for example where R⁵ is halo, C₁-C₄ alkyl, nitro or CF₃. Typical    substituted aryl and substituted heteroaryl groups thus include    3-chloronaphthyl, 4-nitronaphthyl, 4-nitrobenzofuranyl,    3-methylbenzothienyl, and 1-methyl-3-trifluoromethyl indole. These    are compounds of Formula I wherein R is a cyclic, bicyclic or    tricyclic aromatic or heteroaromatic group bearing a substituent    defined as R⁵, where R is other than hydrogen. The group    is a naphthyl ring which can be attached to the amide nitrogen (of    Formula I) at any ring position. This ring can be substituted at any    available ring position by the group R⁵. Specific examples include:    Specific examples of the group:    Specific examples of the group:    Specific examples of the group:    Specific examples of the group: include    Specific examples of the group:    Specific examples of the group:    Specific examples of the group:    Specific examples of the group:    Specific examples of the group:

The compounds of this invention are amines and as such they readily formpharmaceutically acceptable salts by reaction with common inorganic andorganic acids. Typical acids commonly used to form salts includehydrochloric, nitric, phosphoric, and sulfuric acid, as well as acetic,citric, malonic, tartaric, succinic, salicylic, methanesulfonic, oxalicand benzoic acid. Any common inorganic or organic acid can be utilizedto form the pharmaceutically acceptable salts of this invention, and thespecific acid to be utilized is well within the skill of the art.The compounds provided by this invention can be prepared by any ofseveral methods well known to those of ordinary skill in the art oforganic chemistry. In a typical synthesis, an N-aryl alkyl diamine isacylated, for example by reaction with an aryl halide, or by coupling anaryl-acid to the amide in the presence of a common peptide couplingreagent such as DCC (dicyclohexylcarbodiimide). Such synthesis can beillustrated by Scheme 1, in which an alkyl diamine is first prepared byreacting a halo substituted acyl halide with an amine HNR²R³, to givethe corresponding halo substituted amide, reacting the halo substitutedamide with an aryl amine ArNH₂ to give an arylaminoamide, reducing theamide carbonyl to give the corresponding arylamino alkylamine, and thenacylating the arylamino nitrogen atom to give a compound of Formula II.The synthetic sequence is illustrated in scheme 1:

An alternative method for preparing the invention compounds comprisesalkylating a terminal primary or secondary amine of the formula

where one or both of R² and R³ are hydrogen, by reaction with analkylating agent such as an alkyl halide. The reaction is depicted byscheme 2, which illustrates the synthesis of the primary or secondaryamine according to the general scheme shown above, followed by areaction with a common alkylating agent.

In the above scheme, the halo substituted acid halide is reacted with anamine bearing a group that is easily removed, such as benzyl. This is anormal acylation reaction that is typically carried out in a solventsuch as dichloromethane or toluene, and generally is complete within 30min to 1 h when carried out at a temperature of about 30° C. to about60° C. The resulting amide is readily isolated by removing the solvent,and is subsequently reacted with an amine R⁴NH₂ in the presence of abase such as sodium carbonate or triethylamine, and typically in asolvent such as N,N-dimethylformamide or diethyl ether. The resultingamino substituted amide is readily isolated by removing the solvent, andfurther purification generally is not required. The amino substitutedamide is readily reduced by reaction with a reducing agent such aslithium aluminium hydride or sodium borohybride, thus affording analkylene diamine. The alkylene diamine is coupled to an acyl group, forexample by common acylation with an acid anhydride or acid halide (e.g.R¹—C(═O)—O—C(═O)—R or R¹—C(═O)-halo, or by reacting the free acid R¹COOHwith the amine using a coupling reagent such as dicyclohexylcarbodiimide(DCC).The corresponding amide is next converted to a primary or secondaryamine, for instance by removing a group such as benzyl by normalcatalytic hydrogenation. The resulting amine is reacted with a commonalkylating agent such as an alkyl halide (R³-halo) and the resultingproduct of Formula I is isolated by removing any reaction solvent andexcess alkylating agent. The invention compound can be further purifiedif desired by routine methods such as crystallization, for example fromsolvents such as methanol, diethylether, ethyl acetate and the like, orchromatography over solid supports such as silica gel.

Still another way to prepare the invention compounds is to start with anaryl amine (R⁴NH₂), acylate it with and acyl halide or anhydride to forman amide, and then alkylate the amide with an amino substituted alkylhalide. This process is depicted in Scheme 3 below:

These reactions are carried out under normal organic syntheticconditions. For example, an aryl amine such as 3-naphthylamine can bereacted with acetyl chloride in a solvent such as toluene. A base suchas triethylamine can be utilized as an acid scavenger if desired. Thereaction is substantially complete within 1 to 2 h when carried out atabout 30 to 60° C., and the product amide is readily isolated byremoving the reaction solvent. The amine is then alkylated by reactionwith an amino substituted amino alkyl halide to produce the inventioncompound of Formula I.

The synthesis of specific invention compounds is further illustrated bythe following detailed example. The examples are representative only,and are not intended to limit the invention in any respect.

EXAMPLE 1

Reagents: (i) propionyl chloride, Et₃N (ii) NaH, Et₂NCH₂CH₂Cl.HCl

N-Propionyl 1-amino-4-chloronaphthalene.

To a stirred solution of 1-amino-4-chloronaphthalene (0.70 g, 3.9 mmol)in dichloromethane (50 ml) was added triethylamine (1.0 ml, 7 mmol),followed by propionyl chloride (0.5 ml, 5.8 mmol). After 20 min themixture was diluted with ethyl acetate (150 ml) and washed with 2N HCl(100 ml) followed by saturated sodium carbonate (100 ml). The organicphase was separated, dried (MgSO₄) and the solvent removed in vacuo. Theresidue was triturated with a mixture of ethyl acetate and heptane, 130ml, 3:10) to give 0.62 g (67%) of the desired compound as a white solid.

¹H NMR 400 MHz (CDCl₃): ™ 1.33 (3H, t, J=6 Hz); 2.56 (2H, q, J=6 Hz);7.47 (11H, br s); 7.52-7.70, 4H, m); 7.84 (1H, m); 8.32 (1H, m).

MS ES⁺: m/z 236 ([MH⁺], 16%), 234 ([MH]⁺, 48%).

IR (thin film) └_(max) (cm⁻): 1652, 2922, 3300.

N-Propionyl, N-(2-diethylaminoethyl)-1-amino-4-chloronaphthalene.

To a stirred solution of N-propionyl 1-amino-4-chloronaphthalene (400mg, 1.7 mmol) in dry dimethylformamide (40 ml) was added sodium hydride(60% dispersion in oil, 0.2 g, 5 mmol). After 20 min,2-diethylaminoethylchloride hydrochloride (0.4 g, 2.8 mmol) was addedand the mixture stirred for a further 2 h. Water (200 ml) was added andthe mixture extracted with ethyl acetate (2×100 ml). The organicextracts were combined, dried (MgSO₄) and the solvent removed in vacuo.The residue was purified by reverse phase chromatography (methanol:water7:3) to give 0.27 g (47%) of the desired product as a colorless oil.

¹H NMR 400 MHz (CDCl₃): ™ 0.97 (9H, m); 1.80 (1H, m); 2.01 (1H, m); 2.50(4H, m); 2.69 (2H, t, J=7 Hz); 3.34 (1H, m); 4.33 (1H, m); 7.36 (1H, d,J=8 Hz); 7.55-7.70 (3H, m); 7.84 (1H, m); 8.34 (1H, d, J=8 Hz).

MS CI: m/z 233 ([MH]⁺, 100%).

IR (thin film) └_(max) (cm⁻): 1667, 2970.

Microanalysis for C₁₉H₂₅N₂OCl Calculated C 68.56% H 7.57% N 8.42% Found68.29% 7.78% 8.20%

EXAMPLE 2

Reagents: (i) propionyl chloride, Et₃N; (ii) NaH, Et₂NCH₂CH₂Cl.HCl

N-Propionyl 4-amino-9-fluorenone.

To a stirred solution of 4-amino-9-fluorenone (0.20 g, 1.0 mmol) indichloromethane (40 ml) was added triethylamine (0.5 ml, 3.5 mmol),followed by propionyl chloride (0.5 ml, 5.8 mmol). After 20 min themixture was diluted with ethyl acetate (150 ml) and washed with 2N HCl(100 ml) followed by saturated sodium carbonate (100 ml). The organicphase was separated, dried (MgSO₄) and the solvent removed in vacuao.The residue was purified by flash chromatography (silica, heptane:ethylacetate 7:3) to give 164 mg (63%) of the desired material as a yellowoil.

¹H NMR 400 MHz (CDCl₃):™ 1.36 (3H, br t); 2.56 (2H, br q); 7.18-7.38(4H, m); 7.41-7.60, (2H, m); 7.71 (1H, d, J=8 Hz); 7.83 (1H, br s).

IR (thin film) ν_(max) (cm⁻): 1659, 1716, 3258.

N-Propionyl, N-(2-diethylaminoethyl)₄-amino-9-fluorenone.

N-propionyl 4-amino-9-fluorenone (158 mg, 0.6 mmol) was dissolved in drydimethylformamide (40 ml) and sodium hydride (60% dispersion in oil, 80mg, 1.2 mmol). After 20 min, 2-diethylaminoethylchloride hydrochloride(250 mg, 1.4 mmol) was added and the mixture was heated to 80° C. After10 min the mixture was cooled to room temperature and diluted with water(20 ml). The mixture was diluted with saturated sodium carbonate (150ml) and the mixture extracted with ethyl acetate (2×70 ml). The organicextracts were combined, dried (MgSO₄) and the solvent removed in vacuo.The residue was purified by flash chromatography (silica,dichloromethane:diethyl ether 9:1, and then 1:4) to give 0.16 g (73%) ofthe desired product as a colorless oil.

¹H NMR 400 MHz (CDCl₃): ™ 0.95 (6H, t, J=7 Hz); 1.05 (3H, t, J=7 Hz);2.08 (2H, m); 2.50 (4H, m); 2.69 (2H, m); 3.34 (1H, m); 4.34 (1H, m);7.30-7.75 (7H, m).

MS CI: m/z 351 ([MH]⁺, 100%).

IR (thin film) ν_(max) (cm⁻): 1652, 1716, 2970.

Microanalysis for C₂₂H₂₆N₂O₂ Calculated C 75.40% H 7.48% N 7.99% Found75.55% 7.57% 7.94%

EXAMPLES 3-15

By following the general procedure of Examples 1 and 2, severaladditional compounds of Formula I were prepared and are described inTable I below.

The compounds of Formula I have been evaluated in standard in vivo andin vitro assays routinely used to measure the ability of test compoundsto interact with the central nervous system of animals, therebyestablishing their utility for treating CNS disorders such as pain,depression, anxiety and schizophrenia. In a typical assay, compounds areevaluated for their ability to bind to the α₂δ submit of the calciumchannel found in animal brain tissue. Significant binding to thisreceptor indicates a compound's analgesic potential.

In another test, compounds were evaluated for their ability to reducethe hyperalgesia effects of carrageenin in the following assay:nociceptive pressure thresholds were measured in the rat paw pressuretest using an analgesimeter (Randall L. O. and Selitto J. J., A methodfor measurement of analgesic activity on inflamed tissue. Arch. Int.Pharmacodyn 4: 409-419, 1957). Male Sprague-Dawley rats (70-90 g) weretrained on this apparatus before the test day. Pressure was graduallyapplied to the hind paw of each rat Nociceptive thresholds weredetermined as the pressure (g) required to elicit paw withdrawal. Acutoff point of 250 g was used to prevent any tissue damage to the paw.On the test day, 2 to 3 baseline measurements were taken before animalswere administered 100 μl of 2% aqueous carrageenin by intraplantarinjection into the right hind paw.

Nociceptive thresholds were taken again 3 h after carrageenin injectionto establish that animals were exhibiting hyperalgesia. Animals wereorally dosed with a compound of Formula I (by gavage) at 3.5 h aftercarrageenin injections and nociceptive thresholds were examined at 1 andat 2 h post-carrageenin.

Table 1 presents the biological activity of representative inventioncompounds when evaluated in the above tests, and in the in vitro α₂δbinding assay as described by Gee et al. in J. Biol. Chem., 1996; 271:5776-5879, incorporated herein by reference.

TABLE 1 Carrageenin induced thermal hyperalgesia in the rat IC₅₀ (μM) %MPE* % MPE* at α₂δ 1 h post 2 h post binding dose @ dose @ CompoundStructure site 30 mg/kg p.o. 30 mg/kg p.o. N-Propionyl,N-(2-Diethylaminoethyl)-1-amino-4-chloronaphthalene (Example 1)

0.170 51.5 22.2 N-Propionyl,N-(2-Diethylaminoethyl)-4-amino-9-fluorenone (Example 2)

0.058 1.1 6.4 N-Propionyl,N-(2-Diethylaminoethyl)-1-amino-4-bromonaphthalene (Example 3)

0.065 −2.6 7.7 N-Propionyl, N-(N-Morpholino)-1-amino-4-chloronaphthalene(Example 4)

>10 44.8 30.7 N-Propionyl, N-(2-(3-diethylamino-propyl))-1-amino-4-chloronaphthalene (Example 5)

5.03 23.3 27.5 N-Propionyl,N-(2-Diethylaminoethyl)-1-amino-4-azidonaphthalene (Example 6)

0.885 N/A N/A N-Propionyl, N-(2-Diethylaminoethyl)-3-chlorobenzylamine(Example 7)

1.7 N/A N/A N-Propionyl, N-(2-Diethylaminoethyl)-3-bromobenzylamine(Example 8)

4.81 N/A N/A N-Propionyl,N-(2-Piperidylethyl)-1-amino-4-chloronaphthalene (Example 9)

>10 N/A N/A N-Propionyl, N-(2-(3-dimethylaminopropyl))-1-amino-4-chloronaphthalene (Example 10)

2.336 N/A N/A N-Propionyl, N-(2-Dimethylaminoethyl)-1-amino-4-chloronaphthalene (Example 11)

5.34 N/A N/A N-Propionyl, N-(2-(N-benzyl)-aminoethyl)-1-aminonaphthalene(Example 12)

>10 29.68 3.13 N-(2-Diethylaminoethyl)-N-(7-methyl-quinolin-4-yl)-propionamide (Example 13)

5.47 8.6 1.2 N-Acryloyl,N-(2-Diethylaminoethyl)-1-amino-4-chloronaphthalene (Example 14)

0.177 15.1 0.9 N-Propionyl,N-(2-Diethylaminoethyl)-(1-amino-4-nitronaphthalene (Example 15)

0.800 −5.7 2.0 *MPE: maximum possible effect - set as baseline valueprior to treatment with carrageenin

As noted above, the invention compounds of Formula I are typicallyutilized in the form of pharmaceutical compositions for human therapy ofCNS disorders. The compounds can be formulated with any excipient,diluent or carrier commonly utilized in the pharmaceutical art. Suchcommon excipients include potato starch, corn starch, talc, sucrose,lactose, cellulose; flavoring agents such as peppermint, orange flavorand the like. Binders and lubricants such as magnesium stearate,colloidal silicon dioxide and gum tragacanth can be utilized forconvenient oral or parenteral administration, for example as tablets,capsules, aqueous solutions, elixirs, syrups, and controlled releasepatches, pellets and suppositories, as well as solutions for IV, SC andIM injections. The formulations will typically contain from about 5% toabout 95% of active compound of Formula I (w/w).

The preparations will be administered such that the active ingredient ispresented at a dose which is effective to treat a CNS disorder. Suchdose will generally be from about 0.1 to about 2000 mg/kg of bodyweight, typically about 1 mg to about 100 mg/kg. The formulations can beadministered from 1 to about 4 times a day, or as otherwise dictated bythe particular patient and condition being treated, and the attendingmedical practitioner.

The compounds of Formula I can additionally be utilized in combinationwith other active ingredients, for example selective serotonin re-uptakeinhibitors such as fluoxetine hydrochloride, and any of the tricyclicantidepressants such as benzazepines and the like.

The following examples further illustrate specific formulations providedby this invention.

EXAMPLE 16

Tablets N-Butyryl,N-(3-dimethylamino-propyl)-5-amino-indole 200 mgPotato starch  50 mg Magnesium stearate  25 mg Talc  25 mg

The above ingredients are blended to uniformity and then pressed into atablet. Such tablets are administered from 1 to 4 times a day to anadult human suffering from depression and in need of treatment.

EXAMPLE 17

Capsules N-pivaloyl 1-amino-2-trifluoromethyl-naphthalene 300 mg Cornstarch  50 mg Dextrose  50 mg Magnesium oxide  1 mg

The above ingredients are blended to uniformity and filled into an emptytelescoping gelatin capsule. Such capsules are administrated from 1 to 4times a day to an adult human suffering from schizophrenia and in needof treatment.

EXAMPLE 18

Parenteral solution N-propionyl,N-(2-diethylaminoethyl)(1-amino-4- 500mg bromonaphthalene), hydrochloride salt isotonic saline qs 1000 ml

The invention compound is dissolved in 1000 ml of isotonic saline andfilled into a sterile plastic bottle equipped with a drip tube. Thesolution is administered IV to a human suffering from chronic painresulting from colon carcinoma.

EXAMPLE 19

Transdermal skin patch N-acetyl, N-(3-(N-ethyl-N-isobutyl)aminopropyl-450 mg 3-amino-6-bromofluorene propylene glycol  10 mg elastomer  5 mgmethyl cellulose  50 mg sodium carboxymethyl cellulose  25 mgThe above ingredients are blended and spread onto an elastic tape. Thetape is applied to the skin surface of a mammal to prevent and treatmigraine pain.

The compounds of Formula I are useful for treating all conditionsresulting from disorders within the central nervous system in animals,including humans. Commonly treated conditions include pain, depression,anxiety and schizophrenia. Other conditions that can be treatedaccording to this invention include seizure disorders, i.e. epilepsy,Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis(ALS), Alzheimer's disease, migraine, cerebral ischemia, and compulsivedisorders such as narcotic addiction, alcoholism, smoking addiction,appetite disorders such as bulimia and obesity, sexual performance, andsleeping disorders.

1. A compound of formula I

wherein R¹ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; R² and R³independently are hydrogen, C₁-C₄ alkyl, phenyl or benzyl; X is(CH₂)_(n), CHMe-(CH₂)_(n-1) or (CH₂)_(n-1)—CHMe, n is 1, 2 or 3; R⁴ isan aromatic or heteroaromatic group selected from

wherein R⁵ is hydrogen, halogen, C₁-C₄ alkyl, nitro, N₃ or CF₃ and R⁶ ishydrogen, C₁₋₄ alkyl, —

and the pharmaceutically acceptable salts thereof, with the proviso thatin formula I: when R¹ is H, (X)_(n) is (CH₂)₂ and R² and R³ are bothethyl, R⁴ is not benzyl, 4-methylbenzyl, 4-chlorobenzyl, 2-chlorobenzyl,4-bromobenzyl, 3-ethylbenzyl, 4 isopropylbenzyl, 4-n-propylbenzyl,3-n-butylbenzyl, 2-t-butylbenzyl, 4-s-butylbenzyl or 2-bromobenzyl; whenR¹ is H, (X)_(n) is CH_(r) and R⁴ is benzyl, NR²R³ is not NHCH₂Ph,NH-t-butyl, N(CH₃)₂ or N(CH₂CH₃)₂; and when R¹ is n-butyl, (X)_(n) is(CH₂)₂ and R⁴ is benzyl, NR²R³ is not NHCH₂Ph.
 2. A compound accordingto claim 1 wherein R is C₁-C₄ alkyl.
 3. A compound according to claim 2wherein R¹ and R³ independently are C₁-C₄ alkyl.
 4. A compound accordingto claim 3 wherein n is 2 or
 3. 5. A compound according to claim 4wherein R⁴ is selected from


6. A compound according to claim 4 wherein R⁴ is selected from


7. A compound according to claim 4 wherein R⁴ is selected from


8. A compound according to claim 4 wherein R⁴ is selected from


9. N-Propionyl, N-(2-Diethylaminoethyl)-1-amino-4-chloronaphthalene. 10.N-Propionyl, N-(2-Diethylaminoethyl)-4-amino-9-fluorenone. 11.N-Propionyl, N-(2-Diethylaminoethyl)-1-amino-4-bromonaphthalene. 12.N-Propionyl, N-3-diethylamino-2-propyl)-1-amino-4-chloronaphthalene. 13.N-Propionyl, N-(2-Diethylaminoethyl)-1-amino azidonaphthalene. 14.N-Acryloyl, N-(2-diethylaminoethyl)-1-amino-4-chloronaphtnalene. 15.N-Propionyl, N-(2-Diethylaminoethyl)-(1-amino-4-nitronaphthalene).
 16. Acompound according to claim 5 which is selected from N-Propionyl,N-(2-Diethylaminoethyl)-1-amino-4-chloronaphthalene; N-Propionyl,N-(2-Diethylaminoethyl)-4-amino-9-fluorenone; N-Propionyl,N-(2-Diethylaminoethyl)-1-amino-4-bromonaphthalene; N-Propionyl,N-(3-diethylamino-2-propyl)-1-amino-4-chloronaphthalene; N-Propionyl,N-(2-Diethylaminoethyl)-1-4-azidonaphthalene; N-Propionyl,N-(2-Diethylaminoethyl)-3-chlorobenzyl-amine; N-Propionyl,N-(2-Diethylaminoethyl)-3-bromobenzyl-amine; N-Propionyl,N-(2-(3-Diethylamino-propyl)-1-amino-4-chloronaphthalene; N-Propionyl,N-(2 Dimethylaminoethyl)-1-amino-4-chloronaphthalene; N-Propionyl,N-(2-(N-benzyl)-aminoethyl)-1-aminonaphthalene; N-Acryloyl,N-(2-diethylaminoethyl)-1-amino-4-chloronaphthalene; and N-Propionyl,N-(2-Diethylaminoethyl)-(1-amino-4-nitronaphthalene).
 17. A compoundaccording to claim 1 which is a pharmaceutically acceptable salt.
 18. Apharmaceutical formulation comprising a compound of claim 1 togetherwith a pharmaceutically acceptable diluent, carrier or excipienttherefor.
 19. A method for treating a CNS disorder in a mammal in needof treatment comprising administering a CNS effective amount of acompound of claim
 1. 20. A method for treating a CNS disorder in amammal in need of treatment comprising administering a CNS effectiveamount of a compound

wherein: R¹ is hydrogen. C₁₋₄ alkyl, or C₂-C₄ alkenyl; R² and R³independently are hydrogen, C₁-C₄ alkyl, phenyl or benzyl; X is(CH₂)_(n-1), CHMe-(CH₂)_(n-1) or (CH₂)_(n-1)—CHMe, n is 1, 2 or 3; R⁴ isam aromatic or heteroaromatic group selected from

wherein R⁵ is hydrogen, halogen, C₁-C₄ alkyl, nitro, N₃ or CF₃ and R⁶ ishydrogen, C₁₋₄ alkyl, —

and the pharmaceutically acceptable salts thereof.
 21. A methodaccording to claim 19 wherein the CNS disorder is selected from pain,depression, anxiety, or schizophrenia.
 22. A method according to claim19 wherein the CNS disorder is selected from Huntington's disease,Alzheimer's disease or amyotrophic lateral sclerosis.